DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
2. Applicant’s response filed on October 24, 2025 has been entered.
Claims 1-5, 9, 25, 27-36, 38-47, and 51-59 are pending.
Claims 1-5 and 9 are under examination.
Claims 25, 27-36, 38-47, and 51-59 remain withdrawn from consideration as being drawn to a nonelected invention. It is noted that the status identifier of claim 53 is incorrect. This claim should be listed as “Previously presented/Withdrawn.”
Information Disclosure Statement
3. The Information Disclosure Statement filed on October 24, 2025 has been considered.
Response to Arguments
4. Applicant’s arguments filed on October 24, 2025 have been fully considered.
Objection to claim 1
Applicant argues that the objection should be withdrawn in view of the amendments to claim 1 (Remarks, page 7).
This argument was persuasive. The objection has been withdrawn.
Rejection of claims 1 and 9 under 35 U.S.C. 101
Applicant argues that the rejection should be withdrawn in view of the amendments to independent claim 1 (Remarks, pages 7-8). More specifically, Applicant argues that the oligonucleotide sequences currently recited in claim 1 do not occur in nature and are markedly different from any naturally occurring counterpart because the 3’ end of each sequence is mismatched compared to naturally occurring sequences (Remarks, pages 7-8).
This argument was not persuasive because, as discussed in the modified rejection, SEQ ID NOs: 28, 29, and 32 are, in fact, found in naturally occurring sequences. The rejection has been maintained with modifications to address the amendments to claim 1.
Rejection of claims 2-8 under 35 U.S.C. 112(b)
Applicant argues that the rejection should be withdrawn in view of the amendments to claims 2 and 3 (Remarks, page 8).
This argument was persuasive. The rejection has been withdrawn.
Rejection of claim 1 under 35 U.S.C. 102(a)(1) as being anticipated by Kim
Applicant argues that the rejection should be withdrawn in view of the amendments to claim 1 (Remarks, pages 8-9).
This argument was persuasive. The rejection has been withdrawn.
Rejection of claims 2-9 under 35 U.S.C. 103 as being unpatentable over Kim in view of Becker
Applicant argues that the rejection should be withdrawn (Remarks, pages 9-12). More specifically, Applicant first argues that the rejection should be withdrawn because neither Kim nor Becker teaches or suggests a probe with one of the required sequences (i.e., one of SEQ ID NOs: 28-33 (Remarks, page 10). Applicant also argues that the claimed invention is associated with unexpected results—specifically unexpectedly high detection sensitivity and specificity, pointing to Examples 1-3 and 5 as well as Figures 1A-1F, 2A-2B, and 3A-3B for support (Remarks, pages 10-12).
These arguments have been fully considered, but they were not persuasive.
More specifically, Applicant’s first argument was not persuasive because, as discussed in the modified rejection, the teachings of Kim in view of Becker do suggest a probe with the required features. Briefly, Kim identifies in Table 3 regions of the 23S rRNA of T. pallidum that are suitable targets for probe hybridization. Becker provides motivation to convert the linear probes of Kim into molecular torch probes, and as discussed in the rejection, such probes may contain one of the target-hybridizing portions identified in Kim as well as a 3’ portion that hybridizes to a portion of the target-hybridizing portion to form the torch structure.
Applicant’s second argument was also unpersuasive because the results shown in the cited examples and figures are not commensurate in scope with the claimed invention, nor is it clear that they were unexpected. As discussed in MPEP 716.02, especially MPEP 716.02(b) and 716.02(d), respectively, unexpected results must actually be unexpected and said results must be commensurate in scope with the claimed invention. In this case, the examples and associated figures demonstrate that each of SEQ ID NOs: 28-33 provides sensitive and specific results when used as a molecular torch probe in combination with particular oligonucleotide primer pairs (see, e.g., Tables 1 and 3 as well as pages 45-52). It is not clear, though, as to what results would have been reasonably expected. Therefore, the disclosed results cannot clearly be said to be unexpected. As well, the claimed invention is much broader compared to the working examples and associated figures for at least the following reasons: (i) the molecular torch structure of the probes used in the examples is only required by claims 3-5; (ii) all of the claims, including claims 3-5, encompass the use of oligonucleotides that are much longer than SEQ ID NOs: 28-33; and (iii) the results were obtained by using the disclosed probes in an amplification reaction conducted with particular primer pairs, whereas the claims only recite a probe. It is not clear that the observed results, even if they are unexpected, would extend over the full scope of the claimed invention.
Request for Rejoinder
Applicant’s request for rejoinder on page 12 of the Remarks is acknowledged. Since the elected invention is not yet allowable, the withdrawn claims are not eligible for rejoinder. Rejoinder will be considered in accordance with the guidance set forth in MPEP 821.04 when the elected invention is allowable.
Claim Interpretation
5. Applicant has provided explicit definitions for various terms used in the claims and specification. These definitions include the following:
RNA and DNA equivalent bases = nucleotide bases having the same complementary base pair hybridization properties in RNA and DNA (page 15, para. 52). This paragraph further provides uracil and thymine as an example of such equivalent bases.
Claim Rejections - 35 USC § 101
6. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception—specifically, a product of nature—without significantly more.
Claim 1
Claim 1 is drawn to an oligonucleotide hybridization probe. The probe is at least 17 nucleotides in length and comprises SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, or SEQ ID NO: 33. RNA and DNA equivalent bases as defined above may be present. The probe also comprises a detectable label.
As discussed in MPEP 2106.04(b)(II), products of nature include naturally occurring products and non-naturally occurring products that lack markedly different characteristics from any naturally occurring counterpart. In this case, it is not clear that the claimed oligonucleotide probe is found in nature, but the nucleotide sequence of the claimed oligonucleotide probe need not have any sequence differences relative to its naturally occurring counterpart, which is a naturally occurring sequence comprising one of the claimed sequences. See MPEP 2106.04(c)(II)(A), which discusses how to select the naturally occurring counterpart for a short, single-stranded nucleic acid fragment, such as a primer or probe, and states that the appropriate counterpart for such a nucleic acid is the corresponding sense or antisense strand of the naturally occurring sequence. See also the alignments at the end of the rejection, in which a portion of various naturally occurring sequences (“Db” in the alignment) is identical to one of the instant SEQ ID NOs: 28, 29, or 32 (“Qy” in the alignment).
As well, the detectable label recited in the claim need not be a non-naturally occurring element. In para. 46 on page 13 of the specification, the term “detectable label” is noted to include nucleotide sequences. Therefore, the oligonucleotide probe may simply contain more of the naturally occurring counterpart sequence, which would not result in a structural difference relative to the naturally occurring counterpart. There is also no functional difference between the claimed probe and its naturally occurring counterpart because both nucleic acids perform the same function of hybridization to a complementary nucleic acid sequence. See also MPEP 2106.04(c)(II)(C)(2), which discusses why primers are lack markedly different characteristics. The same reasoning set forth there applies here. Thus, claim 1 is directed to a judicial exception.
This judicial exception is not integrated into a practical application because there are no other limitations in the claim besides the judicial exception. As well, since the claim only recites the judicial exception, the claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception. Accordingly, the probe of claim 1 is rejected under 35 U.S.C. 101 as being directed to ineligible subject matter.
Claim 9
Claim 9 depends from claim 1 and further requires the oligonucleotide hybridization probe to include a ribofuranosyl moiety with a 2’-O-methyl substitution. This claim is also directed to a judicial exception because 2’-O-methyl nucleotides occur in naturally occurring nucleic acids. See, e.g., Klein & Klootwijk (Analytical Biochemistry 1976; 74: 263-272; cited previously) at the abstract and page 263 for example. See also Marchand et al. (Nucleic Acids Research 2016; 44: e135; cited previously) at the abstract and page 1, for example. Thus, there need not be any structural differences between the claimed nucleic acid and its naturally occurring counterpart. There are also no functional differences since the claimed probe and its naturally occurring counterpart share the same function of hybridizing to complementary nucleic acids. The judicial exception is not integrated into a practical application because there are no other limitations in the claim besides the judicial exception. As well, since the claim only recites the judicial exception, the claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Thus, the probe of claim 9 is also rejected under 35 U.S.C. 101 as being directed to ineligible subject matter.
SEQ ID NO: 28 alignment with naturally occurring sequence:
RESULT 6
BC021773
LOCUS BC021773 2118 bp mRNA linear ROD 24-FEB-2004
DEFINITION Mus musculus galactosidase, beta 1-like, mRNA (cDNA clone MGC:28635
IMAGE:4222994), complete cds.
ACCESSION BC021773
VERSION BC021773.1
KEYWORDS MGC.
SOURCE Mus musculus (house mouse)
ORGANISM Mus musculus
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha;
Muroidea; Muridae; Murinae; Mus; Mus.
REFERENCE 1 (bases 1 to 2118)
AUTHORS Strausberg,R.L., Feingold,E.A., Grouse,L.H., Derge,J.G.,
Klausner,R.D., Collins,F.S., Wagner,L., Shenmen,C.M., Schuler,G.D.,
Altschul,S.F., Zeeberg,B., Buetow,K.H., Schaefer,C.F., Bhat,N.K.,
Hopkins,R.F., Jordan,H., Moore,T., Max,S.I., Wang,J., Hsieh,F.,
Diatchenko,L., Marusina,K., Farmer,A.A., Rubin,G.M., Hong,L.,
Stapleton,M., Soares,M.B., Bonaldo,M.F., Casavant,T.L.,
Scheetz,T.E., Brownstein,M.J., Usdin,T.B., Toshiyuki,S.,
Carninci,P., Prange,C., Raha,S.S., Loquellano,N.A., Peters,G.J.,
Abramson,R.D., Mullahy,S.J., Bosak,S.A., McEwan,P.J.,
McKernan,K.J., Malek,J.A., Gunaratne,P.H., Richards,S.,
Worley,K.C., Hale,S., Garcia,A.M., Gay,L.J., Hulyk,S.W.,
Villalon,D.K., Muzny,D.M., Sodergren,E.J., Lu,X., Gibbs,R.A.,
Fahey,J., Helton,E., Ketteman,M., Madan,A., Rodrigues,S.,
Sanchez,A., Whiting,M., Madan,A., Young,A.C., Shevchenko,Y.,
Bouffard,G.G., Blakesley,R.W., Touchman,J.W., Green,E.D.,
Dickson,M.C., Rodriguez,A.C., Grimwood,J., Schmutz,J., Myers,R.M.,
Butterfield,Y.S., Krzywinski,M.I., Skalska,U., Smailus,D.E.,
Schnerch,A., Schein,J.E., Jones,S.J. and Marra,M.A.
TITLE Generation and initial analysis of more than 15,000 full-length
human and mouse cDNA sequences
JOURNAL Proc. Natl. Acad. Sci. U.S.A. 99 (26), 16899-16903 (2002)
PUBMED 12477932
REFERENCE 2 (bases 1 to 2118)
AUTHORS Strausberg,R.
TITLE Direct Submission
JOURNAL Submitted (18-JAN-2002) National Institutes of Health, Mammalian
Gene Collection (MGC), Cancer Genomics Office, National Cancer
Institute, 31 Center Drive, Room 11A03, Bethesda, MD 20892-2590,
USA
REMARK NIH-MGC Project URL: http://mgc.nci.nih.gov
COMMENT Contact: MGC help desk
Email: cgapbs-r\@mail.nih.gov
Tissue Procurement: Jeffrey E. Green, M.D.
cDNA Library Preparation: Life Technologies, Inc.
cDNA Library Arrayed by: The I.M.A.G.E. Consortium (LLNL)
DNA Sequencing by: Baylor College of Medicine Human Genome
Sequencing Center
Center code: BCM-HGSC
Web site: http://www.hgsc.bcm.tmc.edu/cdna/
Contact: amg\@bcm.tmc.edu
Gunaratne, P.H., Garcia, A.M., Lu, X., Hulyk, S.W., Loulseged, H.,
Kowis, C.R., Sneed, A.J., Martin, R.G., Muzny, D.M., Nanavati,
A.N., Gibbs, R.A.
Clone distribution: MGC clone distribution information can be found
through the I.M.A.G.E. Consortium/LLNL at: http://image.llnl.gov
Series: IRAK Plate: 37 Row: k Column: 2
This clone was selected for full length sequencing because it
passed the following selection criteria: Similarity but not
identity to protein.
FEATURES Location/Qualifiers
source 1..2118
/organism="Mus musculus"
/mol_type="mRNA"
/strain="FVB/N"
/db_xref="taxon:10090"
/clone="MGC:28635 IMAGE:4222994"
/tissue_type="Kidney, normal. 5 month old male mouse."
/clone_lib="NCI_CGAP_Kid14"
/lab_host="DH10B"
/note="Vector: pCMV-SPORT6"
gene 1..2118
/gene="Glb1l"
/db_xref="GeneID:74577"
/db_xref="MGI:MGI:1921827"
CDS 5..1945
/gene="Glb1l"
/codon_start=1
/product="Glb1l protein"
/protein_id="AAH21773.1"
/db_xref="GeneID:74577"
/db_xref="MGI:MGI:1921827"
/translation="MPPDLPSLLLRLVVLLLLSQAEARSFVVDREHDRFLLDGVPFRY
VSGSLHYFRVPPVLWADRLLKMQLSGLNAVQFYVPWNYHEPEPGIYNFNGSRDLIAFL
NEAAKVNLLVILRPGPYICAEWEMGGLPSWLLRNPNIHLRTSDPAFLEAVDSWFKVLL
PKIYPFLYHNGGNIISIQVENEYGSYKACDFKYMRHLAGLFRALLGDKILLFTTDGPH
GLRCGSLQGLYTTIDFGPADNVTRIFSLLREYEPHGPLVNSEYYTGWLDYWGQNHSTR
SSPAVAQGLEKMLKLGASVNMYMFHGGTNFGYWNGADEKGRFLPITTSYDYDAPISEA
GDPTPKLFAIRNVISKFQEIPLGPLPPPSPKMKFGPLTMSLDGNLLSFLDFLCPQGPI
HSVLPLTFEAVKLDHGFMLYRTYLTSPVLEPTPFWVPNNGIHDRAYVMVDGVLKGVLE
RSLKQELYLTGTVGTRLDILLENMGRLSFGSNHSDFKGLLEAPLLGQTILTEWMMFPL
KVDKLVKWWFPLQLMKRALPQASSVPAFYSAKFPVFGLLGDTFLYLPGWTKGQVWING
FNLGRYWTMRGPQQTLYVPRLLLFGRSINKITLLELENVPHNPQVQFLDKPILNSTLH
WGYNFLLSETQGSFEPMELSGH"
misc_feature 86..1822
/gene="Glb1l"
/note="Glyco_hydro_35; Region: Glycosyl hydrolases family
35"
/db_xref="CDD:pfam01301
Query Match 100.0%; Score 17; Length 2118;
Best Local Similarity 76.5%;
Matches 13; Conservative 4; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCCUUCCUGAAUGAGGC 17
|||::||:|||:|||||
Db 302 GCCTTCCTGAATGAGGC 318
SEQ ID NO: 29 alignment with naturally occuring sequence:
RESULT 4
OZ195138s1
LOCUS OZ195138s1 12010020 bp DNA linear INV 24-OCT-2024
COMMENT segment of length 12010020: from 1 to 12010020
DEFINITION Erebia oeme genome assembly, chromosome: 2.
ACCESSION OZ195138
VERSION OZ195138.1
DBLINK BioProject: PRJEB81338
BioSample: SAMEA115768750
Sequence Read Archive: ERR13800477, ERR13802621
KEYWORDS .
SOURCE Erebia oeme (bright-eyed ringlet)
ORGANISM Erebia oeme
Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta;
Pterygota; Neoptera; Endopterygota; Lepidoptera; Glossata;
Ditrysia; Papilionoidea; Nymphalidae; Satyrinae; Erebiini; Erebia.
REFERENCE 1
CONSRTM Wellcome Sanger Tree of Life Programme
TITLE Direct Submission
JOURNAL Submitted (16-OCT-2024) WELLCOME SANGER INSTITUTE, Tree of Life,
Wellcome Genome Campus, Hinxton CB10 1SA, United Kingdom
COMMENT The assembly ilEreOeme1.hap2.1 is based on 29x PacBio data and
Arima2 Hi-C data generated by Project Psyche
(https://www.projectpsyche.org/). The assembly process included the
following sequence of steps: initial PacBio assembly generation
with Hifiasm in Hi-C integrated assembly mode, and Hi-C based
scaffolding with YaHS. The mitochondrial genome was assembled using
MitoHiFi. Finally, each haplotype assembly was analysed and
manually improved using TreeVal. Chromosome-scale scaffolds
confirmed by the Hi-C data have been named in order of size.
Chromosome Z assigned based on synteny to GCA_964035005.1 (Erebia
palarica).
FEATURES Location/Qualifiers
source 1..37138102
/organism="Erebia oeme"
/mol_type="genomic DNA"
/db_xref="taxon:242259"
/chromosome="2"
assembly_gap 3056167..3056366
/estimated_length=200
/gap_type="unknown"
/linkage_evidence="unspecified"
assembly_gap 3951341..3951540
/estimated_length=200
/gap_type="unknown"
/linkage_evidence="unspecified"
assembly_gap 4229325..4229524
/estimated_length=200
/gap_type="unknown"
/linkage_evidence="unspecified"
assembly_gap 13038553..13038767
/estimated_length=215
/gap_type="unknown"
/linkage_evidence="unspecified"
assembly_gap 15075999..15076198
/estimated_length=200
/gap_type="unknown"
/linkage_evidence="unspecified"
assembly_gap 34646537..34646736
/estimated_length=200
/gap_type="unknown"
/linkage_evidence="unspecified
Query Match 100.0%; Score 18; Length 12010020;
Best Local Similarity 88.9%;
Matches 16; Conservative 2; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CGACAGGGUAAAGCGUCG 18
||||||||:||||||:||
Db 4232484 CGACAGGGTAAAGCGTCG 4232501
SEQ ID NO: 32 alignment with naturally occurring sequence:
RESULT 5
EF192032
LOCUS EF192032 16441 bp DNA circular VRT 25-JUL-2016
DEFINITION Parajulis poecilepterus mitochondrion, complete genome.
ACCESSION EF192032
VERSION EF192032.2
KEYWORDS .
SOURCE mitochondrion Parajulis poecilepterus
ORGANISM Parajulis poecilepterus
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Actinopterygii; Neopterygii; Teleostei; Neoteleostei;
Acanthomorphata; Eupercaria; Labriformes; Labridae; Parajulis.
REFERENCE 1 (bases 1 to 16441)
AUTHORS Oh,D.-J., Kim,J.-Y., Lee,J.-A. and Jung,Y.-H.
TITLE Complete mitochondrial genome of the multicolorfin rainbowfish
Halichoeres poecilopterus (Perciformes, Labridae)
JOURNAL Korean J. Genet. 29 (1), 65-72 (2007)
REFERENCE 2 (bases 1 to 16441)
AUTHORS Jung,Y.-H., Oh,D.-J., Kim,J.-Y. and Lee,J.-A.
TITLE Direct Submission
JOURNAL Submitted (18-DEC-2006) Jeju Biodiversity Research Institute, Jeju
Hi-Tech Industry Development Institute, 4-8 Ara-1, Jeju 690-121,
South Korea
REFERENCE 3 (bases 1 to 16441)
AUTHORS Jung,Y.-H., Oh,D.-J., Kim,J.-Y. and Lee,J.-A.
TITLE Direct Submission
JOURNAL Submitted (24-FEB-2011) Jeju Biodiversity Research Institute, Jeju
Hi-Tech Industry Development Institute, 4-8 Ara-1, Jeju 690-121,
South Korea
REMARK Sequence update by submitter
COMMENT On Feb 24, 2011 this sequence version replaced EF192032.1.
FEATURES Location/Qualifiers
source 1..16441
/organism="Parajulis poecilepterus"
/organelle="mitochondrion"
/mol_type="genomic DNA"
/db_xref="taxon:356780"
tRNA 1..68
/product="tRNA-Phe"
rRNA 69..1015
/product="12S ribosomal RNA"
tRNA 1016..1088
/product="tRNA-Val"
rRNA 1089..2787
/product="16S ribosomal RNA"
tRNA 2788..2861
/product="tRNA-Leu"
/note="codons recognized: UUR"
gene 2862..3836
/gene="ND1"
CDS 2862..3836
/gene="ND1"
/codon_start=1
/transl_table=2
/product="NADH dehydrogenase subunit 1"
/protein_id="ABP03882.1"
/translation="MLSFLTTHIINPLTYIVPILLAVAFLTLIERKVLGYMQMRKGPN
IVGPYGLLQPIADGVKLFIKEPVRPSTSSPVLFLLAPMLALSLALLLWTPMPLPYPVT
DLNLGVLFVLAISSLAVYSILGSGWASNSKYALIGALRAVAQTISYEVSLGLILLNII
IFTGGFTLQTFNTTQESVWLILPAWPLAAMWYISTLAETNRAPFDLTEGESELVSGFN
VEYAGGPFALFFLAEYANILLMNTLSAALFLGASHIPAFPELTAINLMTKAAFLSLLF
LWVRASYPRFRYDQLMHLIWKNFLPITLALIIWHLALPIAFAGLPPQV"
tRNA 3838..3908
/product="tRNA-Ile"
tRNA complement(3908..3978)
/product="tRNA-Gln"
tRNA 3978..4046
/product="tRNA-Met"
gene 4047..5093
/gene="ND2"
CDS 4047..5093
/gene="ND2"
/codon_start=1
/transl_table=2
/product="NADH dehydrogenase subunit 2"
/protein_id="ABP03883.1"
/translation="MNPYITATLLLGLGLGTTITFASSHWLLAWMGLEMNTLAIIPLM
AQHHHPRAVEATTKYFLTQAAAAAMLLFASTTNAWLTGQWDILQMNHPIPLTMITMAL
ALKIGLAPVHSWLPEVLQGLNLTTGLILSTWQKLAPFALLLQLHPSNSTILIILGMAS
TLIGGWGGLNQTQLRKILAYSSIAHLGWMILVLQFSPSLTLLTLLMYFIMTFSTFLVF
KLNDATTMNALSTSWAKTPFIATLTPLVHLSLGGLPPLTGFVPKWLILLELAKQDLPL
IATIAALSALLSLYFYLRLSYAMTLTASPNNVAGMTPWRLPTSQLTLPLAASIAATML
LLPLTPTVFALVMF"
tRNA 5092..5162
/product="tRNA-Trp"
tRNA complement(5166..5234)
/product="tRNA-Ala"
tRNA complement(5236..5308)
/product="tRNA-Asn"
tRNA complement(5347..5414)
/product="tRNA-Cys"
tRNA complement(5415..5484)
/product="tRNA-Tyr"
gene 5486..7036
/gene="CO1"
CDS 5486..7036
/gene="CO1"
/codon_start=1
/transl_table=2
/product="cytochrome c oxidase subunit 1"
/protein_id="ABP03884.1"
/translation="MATTRWLFSTNHKDIGTLYLVFGAWAGMVGTALSLLIRAELSQP
GALLGDDQIYNVIVTAHAFVMIFFMVMPIMIGGFGNWLIPLMIGAPDMAFPRMNNMSF
WLLPPSFLLLLASSGVEAGAGTGWTVYPPLAGNLAHAGASVDLTIFSLHLAGISSILG
AINFITTIVNMKPPAISQYQTPLFVWAVLITAVLLLLSLPVLAAGITMLLTDRNLNTT
FFDPAGGGDPILYQHLFWFFGHPEVYILILPGFGMISHIVAYYAGKKEPFGYMGMVWA
MMAIGLLGFIVWAHHMFTVGMDVDTRAYFTSATMIIAIPTGVKVFSWLATLHGGSIKW
ETPLLWALGFIFLFTVGGLTGIVLANSSLDIVLHDTYYVVAHFHYVLSMGAVFAIVAA
FVHWFPLFTGYTLHSTWTKIHFGVMFVGVNLTFFPQHFLGLAGMPRRYSDYPDAYTLW
NTVSSIGSLISLVAVIMFLFILWEAFAAKREVLTVDLTMTNIEWLHGCPPPYHTFEEP
AFVQVQKK"
tRNA complement(7037..7107)
/product="tRNA-Ser"
/note="codons recognized: UCN"
tRNA 7111..7183
/product="tRNA-Asp"
gene 7190..7880
/gene="CO2"
CDS 7190..7880
/gene="CO2"
/note="TAA stop codon is completed by the addition of 3' A
residues to the mRNA"
/codon_start=1
/transl_except=(pos:7880,aa:TERM)
/transl_table=2
/product="cytochrome c oxidase subunit 2"
/protein_id="ABP03885.1"
/translation="MAHPSQLGFQDAASPVMEELLHFHDHALMIVLLISTLVLYIIVA
MVSTKLTNKYILDSQEIEVIWTILPAVILILIALPSLRILYLMDEINDPHLTIKAMGH
QWYWSYEYTDYEALGFDSYMIPTQDLAPGQFRLLEADHRMVVPVESPIRMLVSAEDVL
HSWAVPALGVKMDAIPGRLNQTAFISSRPGVYYGQCSEICGANHSFMPIVVEAVPLGY
FESWSSLMLEDA"
tRNA 7881..7954
/product="tRNA-Lys"
gene 7960..8127
/gene="ATP8"
CDS 7960..8127
/gene="ATP8"
/codon_start=1
/transl_table=2
/product="ATPase subunit 8"
/protein_id="ABP03886.1"
/translation="MPQLNPAPWFTILIFSWMIFLIVIPPKVMAHTFPYEPTPQSAEK
PKTDSWNWPWH"
gene 8118..8801
/gene="ATP6"
CDS 8118..8801
/gene="ATP6"
/codon_start=1
/transl_table=2
/product="ATPase subunit 6"
/protein_id="ABP03887.1"
/translation="MTLSFFDQFMSPVFLGIPLIALALTLPWILFPTPTSRWLNNRLL
ALQSWFINRFTQQLLLPLSLGGHKWAILLTSLMLFLISLNMLGLLPYTFTPTTQLSLN
MGLAVPLWLATVLIGLRNQPTIALGHLLPEGTPTPLIPVLIIIETISLFIRPLALGVR
LTANLTAGHLLIQLIATAAFVLMPLMPTVAILTGTLLFLLTLLEVAVAMIQAYVFVLL
LSLYLQENV"
gene 8801..9586
/gene="CO3"
CDS 8801..9586
/gene="CO3"
/codon_start=1
/transl_table=2
/product="cytochrome c oxidase subunit 3"
/protein_id="ABP03888.1"
/translation="MAHQAHAYHMVDPSPWPLTGAVAALLMTSGLAIWFHFNSVILMS
LGTILLLLTMYQWWRDIVREGTFQGHHTPPVQKGLRYGMILFITSEVFFFLGFFWAFY
HSSLAPTPELGGCWPPTGITTLDPFEVPLLNTAVLLASGVTVTWAHHSIMEGKRKQAI
QSLFLTIILGFYFTFLQGLEYYEAPFTIADGVYGSTFFVATGFHGLHVIIGSTFLAVC
LVRQIQYHFTSTHHFGFEAAAWYWHFVDVVWLFLYISIYWWGS"
tRNA 9586..9657
/product="tRNA-Gly"
gene 9659..10012
/gene="ND3"
CDS 9659..10012
/gene="ND3"
/codon_start=1
/transl_table=2
/product="NADH dehydrogenase subunit 3"
/protein_id="ABP03889.1"
/translation="MTSLITICISIAVLLALILAIVSFWLPQMTPDYEKLSPYECGFD
PLGSARLPFSLRFFLVAILFLLFDLEIALLLPLPWGDQLASPLTTFFWAAMVLVLLTI
GLIYEWIQGGLEWAE"
tRNA 10011..10079
/product="tRNA-Arg"
gene 10080..10376
/gene="ND4L"
CDS 10080..10376
/gene="ND4L"
/codon_start=1
/transl_table=2
/product="NADH dehydrogenase subunit 4L"
/protein_id="ABP03890.1"
/translation="MTPFQFAFSAAFTLGLTGLTFHRTHLLSALLCLEGMMLSLFIAL
SLWTLQLSSPNFSSAPMLLLAFSACEAGAGLALLVATARTHGTDRLQNLNLLQC"
gene 10370..11749
/gene="ND4"
CDS 10370..11749
/gene="ND4"
/codon_start=1
/transl_table=2
/product="NADH dehydrogenase subunit 4"
Query Match 100.0%; Score 17; Length 16441;
Best Local Similarity 70.6%;
Matches 12; Conservative 5; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCCUUGUCAUUGCAGGC 17
|||::|:||::||||||
Db 11256 GCCTTGTCATTGCAGGC 11272
Claim Rejections - 35 USC § 112
7. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5 and 9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to require the oligonucleotide hybridization probe to comprise a “a sequence comprising SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, or SEQ ID NO: 33, allowing for substitution of RNA and DNA equivalent bases; and a detectable label.” The claim has also been amended to remove the previous requirement for the hybridization probe to be “up to 47 bases in length.”
Applicant’s response identifies para. 178 and Table 1 on page 46 of the originally filed specification as providing support for this subject matter (Remarks, page 7).
The original disclosure, including the portions cited by Applicant, has been reviewed, but support was not found for the full scope of amended claim 1. The claim, as amended, is no longer limited to probes that are no more than 47 bases in length and encompasses much longer oligonucleotides comprising one of the recited sequences since the specification defines “oligonucleotide” as “a nucleic acid of generally less than 1,000 nucleotides” (para. 43) and does not define “hybridization probe” in a way that limits its length. The original disclosure, though, only provides support for hybridization probes that are up to 100 nucleotides in length (see, e.g., original claim 1 and paras. 7, 11, 20, and 148). Table 1 and para. 178 do not provide support for the full scope of amended claim 1 because they only provide support for hybridization probes consisting of one of the recited sequences and a detectable label. That is, Table 1 and para. 178 do not provide support for the much longer hybridization probes encompassed by the amended claim. Accordingly, amended claim 1 contains new matter.
Claims 2-5 and 9 also contain new matter since they depend from claim 1 and do not correct its new matter issue.
Claim Rejections - 35 USC § 103
8. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
9. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
10. Claims 1-5 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (US 2008/0261206 A1) in view of Becker et al. (US 2009/0181395 A1).1
Claim 1, from which claims 2-5 and 9 depend, is drawn to an oligonucleotide hybridization probe that comprises a sequence comprising one of SEQ ID NOs: 28-33 as well as a detectable label. As can be seen in Table 1 on page 46 of the specification of the instant application, SEQ ID NOs: 28-33 are molecular torch probes, and thus contain a nucleotide sequence that hybridizes to Treponema pallidum as well as a 3’ sequence that forms a “closing domain” that hybridizes to the 5’ portion of the probe. For example, in SEQ ID NO: 28, nucleotides 1-14 hybridize to T. pallidum, and nucleotides 14-17 are capable of hybridizing to nucleotides 1-4 to form a “closing domain.”
Regarding claim 1, Kim discloses oligonucleotide hybridization probes that specifically hybridize to Treponema pallidum (see Table 3 on pp. 26-27). The probes may contain a detectable label (e.g., a fluorescent label or a FRET label) (see, e.g., para. 16). The probes in Table 3 of Kim also include probes that contain the target-hybridizing (i.e., T. pallidum-specific) sequence in the instant SEQ ID NOs: 28-30, 32, and 33. More specifically, SEQ ID NO: 1306 of Kim comprises nucleotides 1-14 of the instant SEQ ID NO: 28. SEQ ID NO: 1305 of Kim comprises nucleotides 1-14 of the instant SEQ ID NO: 29 and nucleotides 1-16 of the instant SEQ ID NO: 30. SEQ ID NOs: 1305 and 1306 of Kim each comprise nucleotides 1-13 of the instant SEQ ID NO: 32, and SEQ ID NO: 1307 of Kim comprises nucleotides 1-22 of the instant SEQ ID NO: 33.2
Regarding claims 2-4, as noted above, Kim teaches that the disclosed probes may contain a label (para.16). The label may be suitable for FRET (para. 16), which suggests an interactive pair of labels comprising a fluorophore moiety and a quencher moiety.
Kim is not anticipatory for the following reasons. First, Kim does not anticipate claim 1 because the probes of SEQ ID NOs: 1305-1307 do not include the 3’-terminal nucleotides in the instant sequences that form the “closing domain” of a molecular torch probe. Kim also fails to teach that the probes include a 2’-O-methyl substitution required by claims 2 and 9. Further, Kim does not teach that the probes include a non-nucleotide linker as required by claims 3-5 or that the probe is a molecular torch as also required by claims 3-5.
Becker, though, describes oligonucleotide primers and detectably labeled probes for amplifying and detecting target nucleic acids and teaches that molecular torches are useful as probes in homogeneous assays, which do not require physically separating hybridized probes from unhybridized probes prior to detection (paras. 9, 10, 51, and 78). Becker describes the structural features of molecular torches in para. 100 and teaches in this paragraph that these probes contain “distinct regions of self-complementarity (referred to as ‘the target-binding domain’ and the ‘target closing domain’) which are connected by a joining region (e.g., a non-nucleotide linker) and which hybridize to each other under predetermined hybridization assay conditions.” Becker further teaches that “Under strand displacement conditions, hybridization of the two complementary regions…of the molecular torch is favored, except in the presence of the target sequence, which will bind to the single-stranded region present in the target binding domain and displace all or a portion of the target closing domain” (para. 100).
Becker additionally teaches that molecular torch probes also contain a detectable label or a pair of interacting labels (e.g., a luminescent/quencher pair) (para. 100). Becker further notes suitable lengths for the target-binding region (1-20 nucleotides) and describes how the probes function in an assay in addition to pointing to another prior art reference (US 6,534,274) as a source of additional design guidance.
Becker further teaches that a FRET pair containing a fluorophore and quencher is also a suitable interacting label pair for use in a molecular torch (see, e.g., paras. 104-106 and 119). Still further, Becker teaches that probes may contain a 2’-O-methyl substitution as recited in claims 2 and 9 (para. 97) and that the C9 spacer recited in claim 5 is a suitable non-nucleotide linker (para. 119).
Lastly, Becker discloses examples of molecular torch probes in Tables 4-6 on page 18. These probes contain a target-binding sequence, a non-nucleotide linker (C9 spacer), a closing domain sequence, and a FRET pair consisting of a fluorophore and a quencher (para. 119). The closing domain sequence of the probes in Tables 4-6 of Becker ranges from 5-6 nucleotides.
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for the ordinary artisan to design a molecular torch probe comprising a sequence comprising (i) one of the instant SEQ ID NOs: 28-30, 32, or 33; (ii) a C9 linker; and (iii) a pair of interactive labels comprising a fluorophore and quencher pair. More specifically, the ordinary artisan would have been motivated to design a molecular torch probe containing the general structural features set forth in Becker (i.e., target-binding domain, closing domain, non-nucleotide linker, and interactive pair of labels) and also containing one of the aforementioned portions of one of SEQ ID NOs: 1305-1307 of Kim as the T. pallidum-specific target-binding sequence. The ordinary artisan would have been motivated to convert a conventional linear probe of Kim to a molecular torch probe to obtain the ability to perform homogenous assays as described in Becker using a molecular torch probe. The ordinary artisan would have recognized from the teachings in paras. 51 and 78 of Becker that molecular torch probes would offer a more convenient and potentially faster assay by eliminating the need to physically separate hybridized from unhybridized probes prior to detection. The ordinary artisan also would have recognized that removing the need for a physical separation step would also eliminate one source of contamination.
In doing so, the ordinary artisan would have been motivated to use the design guidance provided by Becker and also to incorporate structural features taught by Becker to be useful for inclusion in such probes, namely a non-nucleotide linker (e.g., a C9 spacer), an interacting label pair (e.g., a fluorophore moiety and a quencher moiety), and at least one 2’-O-methyl nucleoside. The ordinary artisan also would have recognized that a molecular torch probe as suggested by Becker should have a closing domain sequence at the 3’ end capable of hybridizing to a portion of the target-binding domain, and accordingly, would have been motivated to add nucleotides at the 3’ end of the sequences. Doing so would result in a probe with all of the required features. The ordinary artisan would have had a reasonable expectation of success in view of the guidance provided throughout Becker concerning the design of molecular torch probes.
Thus, in the absence of persuasive evidence of unexpected results with respect to the claimed probes, the oligonucleotide hybridization probes of claims 1-5 and 9 are prima facie obvious over Kim in view of Becker.
Conclusion
11. No claims are currently allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Angela Bertagna whose telephone number is (571)272-8291. The examiner can normally be reached 8-5, M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681
1 Each of these references was cited in the last Office action.
2 It is noted that the probes of Kim contain thymine rather than the uracil recited in the claimed sequences, but the “allowing for substitution of RNA and DNA equivalent bases” language in claim 1 encompasses sequences in which thymine is substituted for uracil.